The genetic basis of variation in susceptibility to infection with Histoplasma capsulatum in the mouse.

The pathogenic fungus Histoplasma capsulatum causes disease ranging from mild to fatal in healthy and immunocompromised humans. Infection rates reach 80% in endemic areas, including the Midwestern United States. We used inbred mice to identify a 300-fold difference in fungal burden. A/J mice showed lower fungal burden and morbidity than C57BL/6J mice, a reversal of the trend observed for many bacterial pathogens. We mapped the differences in fungal burden to discrete locations on chromosomes 1, 6, 15 and 17 with high significance. Substitution of a single resistant chromosome 17 onto the susceptible background was sufficient to lower fungal burden. These loci will allow dissection of the fungal-specific immune program.

A randomized trial that compared oral cefixime and intramuscular ceftriaxone for the treatment of gonorrhea in pregnancy.

OBJECTIVE: The purpose of this study was to evaluate prospectively the Centers for Disease Control recommendations for the treatment of gonococcal infection in pregnancy. STUDY DESIGN: One hundred sixty-one women who were referred with probable endocervical gonorrhea underwent pretreatment endocervical, anal, and oral cultures for Neisseria gonorrhoeae. The women were randomly assigned to receive ceftriaxone 125 mg intramuscularly or cefixime 400 mg orally. Treatment was open and in a 1:1 distribution. There were 95 evaluable patients. The tests of cure cultures were performed 4 to 10 days after treatment. RESULTS: Eighty-six women (91%) had endocervical infection; 39 women (41%) had anal infection, and 11 women (12%) had pharyngeal infection. Fifty of 95 women (53%) had concomitant endocervical chlamydial infection. The overall efficacy was 91 of 95 subjects (95.8%; 95% CI, 89.6%-98.8%). Ceftriaxone was effective in 41 of 43 cases (95%; 95% CI, 84.2%-99.4%), and cefixime was effective in 50 of 52 cases (96%; 95% CI, 86.8%-99.5%). No significant difference was noted in the overall efficacy or by site of infection. Three of the 4 women who experienced treatment failures admitted to unprotected intercourse before their test of cure culture. CONCLUSION: Both intramuscular ceftriaxone 125 mg and oral cefixime 400 mg appear to be effective for the treatment of gonococcal infection in pregnancy.

Trends in peripheral vascular procedures in the Veterans Health Administration, 1989-1998.

OBJECTIVE: To assess trends in peripheral vascular procedures performed in Veterans Health Administration (VHA) facilities. METHODS: All discharges with peripheral vascular procedures recorded for 1989-1998 were analyzed. The VHA user population was used to calculate age-specific rates. Trends were evaluated using frequency tables and Poisson regression. RESULTS: The VHA had 55,916 discharges with peripheral vascular procedures performed almost exclusively in men. Indications included peripheral vascular disease (53.7%), gangrene (19.3%), surgical complications (13.3%), and ulcers and infection (9.6%). The VHA age-specific rates were higher than US population rates for persons 45 to 64 years, similar for those 65 to 74 years, and lower for those 75 years and older. The age-specific rates declined slightly over the 10 years of observation, with the greatest decline noted in men age 45 to 65. CONCLUSION: The VHA provides almost 8% of all US peripheral vascular procedures in males. The VHA age-specific rates differ from the US rates with a shift to younger patients. The rates decreased for all age groups between 1989-1998.

Survival following lower-limb amputation in a veteran population.

GOAL: We sought to describe the common demographic and comorbid conditions that affect survival following nontraumatic amputation. METHODS: Veterans Administration hospital discharge records for 1992 were linked with death records. The most proximal level during the first hospitalization in 1992 was used for analysis. Demographic information (age, race) and comorbid diagnosis (cardiovascular, cerebrovascular, and renal disease) were used for Kaplan-Meier curves to describe survival following amputation. MAIN OUTCOME MEASURE: Death. RESULTS: Mortality risk increased with advanced age, more proximal amputation level, and renal and cardiovascular disease, and decreased for African Americans. No increased risk for persons with diabetes was noted in the first year following amputation but the risk increased thereafter. A higher risk of mortality in the first year was noted for renal disease, cardiovascular disease, and proximal amputation level. CONCLUSION: Survival following lower-limb amputation is impaired by advancing age, cardiovascular and renal disease, and proximal amputation level. Also, a small survival advantage is seen for African Americans and those with diabetes.

Gene families from the Arabidopsis thaliana pollen coat proteome.

The pollen extracellular matrix contains proteins mediating species specificity and components needed for efficient pollination. We identified all proteins >10 kilodaltons in the Arabidopsis pollen coating and showed that most of the corresponding genes reside in two genomic clusters. One cluster encodes six lipases, whereas the other contains six lipid-binding oleosin genes, including GRP17, a gene that promotes efficient pollination. Individual oleosins exhibit extensive divergence between ecotypes, but the entire cluster remains intact. Analysis of the syntenic region in Brassica oleracea revealed even greater divergence, but a similar clustering of the genes. Such allelic flexibility may promote speciation in plants.

Geographic variation of lower-extremity major amputation in individuals with and without diabetes in the Medicare population.

OBJECTIVE: To describe geographic variation in rates of lower-limb major amputation in Medicare patients with and without diabetes. RESEARCH DESIGN AND METHODS: This cross-sectional population-based study used national fee-for-service Medicare claims from 1996 through 1997. The unit of analysis was 306 hospital referral regions (HRRs) representing health care markets for their respective tertiary medical centers. Numerators were calculated using nontraumatic major amputations and the diabetes code (250.x) for individuals with diabetes. Denominators for individuals with diabetes were created by multiplying the regional prevalence of diabetes (as determined using a 5% sample of Medicare Part B data identifying at least two visits with a diabetes code for 1995-1996) by the regional Medicare population. Denominators for individuals without diabetes were the remaining Medicare beneficiaries. Rates of major amputations were adjusted for age, sex, and race. RESULTS: Rates of major amputations per year were 3.83 per 1,000 (95% CI 3.60-4.06) individuals with diabetes compared with 0.38 per 1,000 (95% C1 0.35-0.41) individuals without diabetes. Marked geographic variation was observed for individuals with and without diabetes; however, patterns were distinct between the two populations. Rates were high in the Southern and Atlantic states for individuals without diabetes. In contrast, rates for individuals with diabetes were widely varied. Variation across HRRs for individuals with diabetes was 8.6-fold compared with 6.7-fold in individuals without diabetes for major amputations. CONCLUSIONS: Diabetes-related amputation rates exhibit high regional variation, even after age, sex, and race adjustment. Future work should be directed to exploring sources of this variation.

The use of the Semmes-Weinstein monofilament and other threshold tests for preventing foot ulceration and amputation in persons with diabetes.

OBJECTIVE: To evaluate the evidence supporting the Semmes-Weinstein monofilament (SWM) and other threshold testing in preventing ulcers and amputation. SEARCH STRATEGY: We searched the MEDLINE database using the Medical Subject Headings ("diabetic foot" or "diabetes mellitus" and ["foot ulcer" or "foot diseases"]) and ("sensory threshold" or "touch" or "vibration" or "monofilament [text word]" or "two point discrimination [text word]") restricted to studies with human subjects and published in the English language between 1985 and 2000. DATA ABSTRACTION: The studies were abstracted by one author (J.M.) and confirmed by the second author (J.S.). SELECTION CRITERIA: The studies had to contain original data collection and SWM or another threshold assessment method. DATA COLLECTION/ANALYSIS: All articles were abstracted for study design, testing method, population, and results. MAIN RESULTS: We identified 6 prospective studies using SWMs and 4 with vibration perception thresholds (VPTs), including 1 randomized controlled trial. The increased risk of ulceration ranged from an odds ratio (OR) of 2.2 to 9.99, and the risk of amputation was a relative risk of 2.9 using the SWM and an OR of 4.38 to 7.99 for VPT. The randomized controlled trial of screening plus treatment for those with previous ulcers had no significant decrease in the number of ulcers or minor amputations but showed significantly fewer major amputations. CONCLUSIONS: The SWM is currently the best choice for screening for clinically significant neuropathy because it is portable, inexpensive, painless, easy to administer, acceptable to patients, and provides good predictive ability for the risk of ulceration and amputation. Once the patient without protective sensation has been identified, management with protective footwear and patient education to prevent damage should be instituted but compliance is often difficult to implement.

Alterations in CER6, a gene identical to CUT1, differentially affect long-chain lipid content on the surface of pollen and stems.

Very long chain lipids contribute to the hydrophobic cuticle on the surface of all land plants and are an essential component of the extracellular pollen coat in the Brassicaceae. Mutations in Arabidopsis CER genes eliminate very long chain lipids from the cuticle surface and, in some cases, from the pollen coat. In Arabidopsis, the loss of pollen coat lipids can disrupt interactions with the stigma, inhibiting pollen hydration and causing sterility. We have positionally cloned CER6 and demonstrate that a wild-type copy complements the cer6-2 defect. In addition, we have identified a fertile, intragenic suppressor, cer6-2R, that partially restores pollen coat lipids but does not rescue the stem wax defect, suggesting an intriguing difference in the requirements for CER6 activity on stems and the pollen coat. Importantly, analysis of this suppressor demonstrates that low amounts of very long chain lipids are sufficient for pollen hydration and germination. The predicted CER6 amino acid sequence resembles that of fatty acid-condensing enzymes, consistent with its role in the production of epicuticular and pollen coat lipids >28 carbons long. DNA sequence analysis revealed the nature of the cer6-1, cer6-2, and cer6-2R mutations, and segregation analysis showed that CER6 is identical to CUT1, a cDNA previously mapped to a different chromosome arm. Instead, we have determined that a new gene, CER60, with a high degree of nucleotide and amino acid similarity to CER6, resides at the original CUT1 locus.

Do foot examinations reduce the risk of diabetic amputation?

BACKGROUND: Foot examinations are widely recommended as a means to reduce amputation risk, but no investigators have studied their independent effect on this outcome. METHODS: We conducted a population-based case-control study of primary care provided to Pima Indians from the Gila River Indian Community. Sixty-one Pima Indians with type 2 diabetes and a first lower-extremity amputation between January 1, 1985, and December 31, 1992, were compared with 183 people who had no amputation by December 31, 1992. The type of foot examination conducted, comorbid conditions, and foot risk factors present in the 36 months before the pivotal event were abstracted from medical records. All ulcer care was excluded. The independent effect of foot examinations on the risk of amputation was assessed by logistic regression. RESULTS: During the 36 study months, 1857 foot examinations were performed on 244 subjects. The median number of preventive foot examinations was 7 for case patients and 3 for control patients. After controlling for differences in comorbid conditions and foot risk conditions, the risk of amputation for persons with 1 or more foot examinations was an odds ratio (OR) of 0.55 (95% confidence interval [CI], 0.2-1.7; P=.31). The risk of amputation associated with written comments of nonadherence with therapeutic foot care recommendations or diabetic medication was an OR of 1.9 (95% CI, 0.9-4.3; P=.10). CONCLUSIONS: Our study failed to demonstrate that foot examinations decrease the risk of amputation in Pima Indians with type 2 diabetes. However, foot examinations detect high-risk conditions for which specific interventions have been shown to be effective in reducing amputation risk.

Trends in lower limb amputation in the Veterans Health Administration, 1989-1998.

OBJECTIVE: To assess trends in lower limb amputation performed in Veterans Health Administration (VHA) facilities. METHODS: All lower limb amputations recorded in the Patient Treatment File for 1989-1998 were analyzed using the hospital discharge as the unit of analysis. Age-specific rates were calculated using the VHA user-population as the denominator. Frequency tables and linear, logistic, and Poisson regression were used respectively to assess trends in amputation numbers, reoperation rates, and age-specific amputation rates. RESULTS: Between 1989-1998, there were 60,324 discharges with amputation in VHA facilities. Over 99.9% of these were in men and constitute 10 percent of all US male amputations. The major indications were diabetes (62.9%) and peripheral vascular disease alone (23.6%). The age-specific rates of major amputation in the VHA are higher than US rates of major amputation. VHA rates of major and minor amputation declined an average of 5% each year, while the number of diabetes-associated amputations remained the same. CONCLUSION: The number and age-specific rates of amputations decreased over 10 years despite an increase in the number of veterans using VHA care.

Work disability and diabetes.

OBJECTIVE: To determine the rates and demographic determinants of work disability, hours worked per week, work-loss days, and wages in individuals with diabetes. RESEARCH DESIGN AND METHODS: A probit regression analysis was performed on a cross-sectional population-based survey of U.S. noninstitutionalized civilian population (National Medical Expenditures Survey--2, 1987). The sample was restricted to individuals aged > or = 25 years. A total of 1,502 individuals reported having diabetes, and 20,405 did not. Information on workforce participation and income were collected quarterly. Work disability was defined as a self-report of having been unable to work because of illness or disability for > or = 2 quarters in 1987. RESULTS: Work disability was reported by 25.6% of individuals with diabetes, compared with 7.8% of those without diabetes. Work disability rates were higher for older people, females, and African-Americans, and lower for Hispanics and for individuals with greater non-wage income. Individuals with diabetes engaged in the workforce had more work-loss days than did nondiabetic individuals, but had similar hourly wages. Predicted mean earnings were significantly lower for individuals with diabetes at all ages, resulting in $4.7 million loss in earnings in 1987 due to work disability. CONCLUSIONS: Work disability is significantly higher for individuals with diabetes than for those without diabetes at all ages, and results in a significant decrease in earnings. A disproportionate burden of work disability is borne by older individuals and women with diabetes. Better information on the determinants of work disability in individuals with diabetes is needed.

Preventive foot care in people with diabetes.

A number of effective, low-cost strategies are available to identify and treat the person at risk for diabetic foot ulcers and lower-extremity amputation. These strategies must be more widely adopted by all diabetic care providers to maintain the integrity and function of the lower limb, and thus improve the quality of life for people with diabetes.

A foot risk classification system to predict diabetic amputation in Pima Indians.

OBJECTIVE: To quantify the contribution of various risk factors to the risk of amputation in diabetic patients and to develop a foot risk scoring system based on clinical data. RESEARCH DESIGN AND METHODS: A population case-control study was undertaken. Eligible subjects were 1) 25-85 years of age, 2) diabetic, 3) 50% or more Pima or Tohono O'odham Indian, 4) lived in the Gila River Indian Community, and 5) had had at least one National Institutes of Health research examination. Case patients had had an incident lower extremity amputation between 1983 and 1992; control subjects had no amputation by 1992. Medical records were reviewed to determine risk conditions and health status before the pivotal event that led to the amputation. RESULTS: Sixty-one people with amputations were identified and compared with 183 control subjects. Men were more likely to suffer amputation than women (odds ratio [OR] 6.5, 95% CI 2.6-15), and people with diabetic eye, renal, or cardiovascular disease were more likely to undergo amputation than those without (OR 4.6, 95% CI 1.7-12). The risk of amputation was almost equally associated with these foot risk factors: peripheral neuropathy, peripheral vascular disease, bony deformities, and a history of foot ulcers. After controlling for demographic differences and diabetes severity, the ORs for amputation with one foot risk factor was 2.1 (95% CI 1.4-3.3), with two risk factors, 4.5 (95% CI 2.9-6.9), and with three or four risk factors, 9.7 (95% CI 6.3-14.8). CONCLUSIONS: Male Sex, end-organ complications of eye, heart, and kidney, and poor glucose control were associated with a higher amputation rate. Peripheral neuropathy, peripheral vascular disease, deformity, and a prior ulcer were similarly equally associated with an increased risk of lower extremity amputation.

A call for specific codes for diabetes foot and eye care.

In this report, we propose new International Classification of Diseases (ICD) codes that could be incorporated into computer-based patient records or administrative data to monitor and improve diabetes care. Neither the ICD, 9th Revision, nor its imminent replacement, the ICD, 10th Revision, has specific codes for foot examinations and funduscopic examinations in the asymptomatic person, high-risk diabetic foot status, or clinically significant macular edema. Adoption of official codes for these procedures and conditions implemented in conjunction with computerized databases could be used for surveillance, program planning, and quality of care assessment. Computerized medical records could use the codes to monitor care and issue reminders to patients and providers. Payors could offer reimbursement incentives to encourage compliance with standard recommendations. These codes for care procedures could be linked to outcomes, such as amputations and blindness, to improve our understanding of the etiology of blindness and the relationship between process and outcome. The uniform adoption of these codes would facilitate comparison between health care systems, geographic regions, and nations. The diabetes community should encourage the National Center for Health Statistics to adopt new codes that could be used to monitor diabetes preventive care practices.

Assessment of diabetes care by medical record review. The Indian Health Service model.

OBJECTIVE: To evaluate the adherence to minimum standards for diabetes care in multiple primary-care facilities using a uniform system of medical record review. RESEARCH DESIGN AND METHODS: In 1986, the Indian Health Service (IHS) developed diabetes care standards and an assessment process to evaluate adherence to those standards using medical record review. We review our assessment method and results for 1992. Charts were selected in a systematic random fashion from 138 participating facilities. Trained professional staff reviewed patient charts, using a uniform set of definitions. A weighted rate of adherence was constructed for each item. RESULTS: Medical record reviews were conducted on 6,959 charts selected from 40,118 diabetic patients. High rates of adherence (> 70%) were noted for blood pressure and weight measurements at each visit, blood sugar determinations at each visit, annual laboratory screening tests, electrocardiogram at baseline, and adult immunizations. Lower rates of adherence (< or = 50%) were noted for annual eye, foot, and dental examinations. CONCLUSIONS: IHS rates of adherence are similar to rates obtained from medical record reviews and computerized billing data, but are less than rates obtained by provider self-report. Medical record review, using uniform definitions and inexpensive software for data entry and reports, can easily be implemented in multiple primary-care settings. Uniformity of data definition and collection facilitates the aggregation of the data and comparison over time and among facilities. This medical record review system, although labor intensive, can be easily adopted in a variety of primary-care settings for quality improvement activities, program planning, and evaluation.

Neonatal mortality clusters: a new tool for classifying neonatal outcomes.

BACKGROUND: A method for assessing general hospital neonatal care performance is needed that is simple, is easy to use, and requires minimal data. METHODS: All neonatal deaths in Washington State obstetric hospitals from 1980 to 1983 were assigned to 10 mutually exclusive neonatal mortality clusters, a new classification method derived from information available on the death certificate. RESULTS: More than one-third (35.3 percent) of all neonatal deaths fell within one of the seven clusters considered to represent potentially preventable causes of death. The rate of possibly preventable deaths was much higher in level III hospitals than in level II or level I hospitals, a finding similar to that observed in other states using different analytic approaches. CONCLUSIONS: Neonatal mortality clusters offer a less complex method of classifying neonatal deaths and assessing hospital performance than other currently used techniques.

The relation of obstetrical volume and nursery level to perinatal mortality.

We investigated the relation of hospital delivery volume and nursery technology level to perinatal outcome in 226,164 White singleton births in Washington State, 1980-83. Level III facilities (neonatal intensive care unit) were defined by the state licensing commission. We defined the Level II (intermediate) and Level I (normal newborn) facilities using published criteria. Infants under 2000 gm born in Level III facilities had half the risk of perinatal death compared to those born in a Level I or II facility. No significant improvement was noted among level or volume groupings for normal birthweight infants. A loglinear regression model of hospital perinatal death rates showed that when birthweight and maternal risk were controlled, obstetrical volume added minimal explanatory power to level of nursery care.

Outcomes of regionalized perinatal care in Washington State.

We evaluated the extent to which the regionalization of perinatal care in Washington State has succeeded in concentrating high-risk pregnancies in technologically appropriate referral centers and in reducing differences in neonatal outcome among hospitals. Of all infants weighing less than 1,500 grams born between 1980 and 1983, nearly 68% were delivered in level III hospitals, although only 24% of all babies are born in these hospitals, indicating that the state is highly regionalized. Neonatal outcomes-as measured by standardized mortality ratios-are similar in level I, II and III hospitals and are not greatly influenced by the rural or urban location of the hospital. The most promising strategy for further reducing neonatal mortality is to decrease the number and proportion of very-low-birth-weight births.